Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc

Abstract

Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as, c-fos, Egr1 and arc are selectively and promptly upregulated in learning and memory among neuronal subpopulations in regions associated with these processes. Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions.

Porcine placental extract facilitates memory and learning in aged mice

“…Four genes were significantly up‐regulated in aged mice treated with SD‐F relative to control, that is, Erg1 , Gadd45b , Nab2 , and Vegfa . These show different cellular localizations; Erg1 and Nab2 are localized in the cell nucleus, Gadd45b is localized to the cytoplasm, and Vegfa is secreted extracellularly (Gallo, Katche, Morici, Medina, & Weisstaub, ; Leach et al, ; Marballi & Gallitano, ; Mateo et al, ). Erg1 is a member of the Erg family of immediate early gene transcription factors and plays an important role in long‐term memory formation and late‐phase long‐term potentiation (LTP) (Cole, Saffen, Baraban, & Worley, ; Worley et al, ).…”

“…and Nab2 are localized in the cell nucleus, Gadd45b is localized to the cytoplasm, and Vegfa is secreted extracellularly (Gallo, Katche, Morici, Medina, & Weisstaub, 2018;Leach et al, 2012 Marballi & Gallitano, 2018;Mateo et al, 2006). Erg1 is a member of the Erg family of immediate early gene transcription factors and plays an important role in long-term memory formation and late-phase long-term potentiation (LTP) (Cole, Saffen, Baraban, & Worley, 1989;Worley et al, 1993).…”

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

“…After activation, SRF propagates in neurons an immediate early gene (IEG) response resulting in rapid (within minutes) but transient upregulation of target genes including cFos, Egr1, Egr2, Egr3, and, for example, Arc . Since many SRF effector genes encode TFs, this results in a second gene expression wave involved in modulation of learning and memory, synaptic plasticity as well as neuro‐behavioral changes such as hyperactivity and modulated anxiety . So far, selected IEGs such as cFos, cJun, and Egr1 were found upregulated by TBI in humans and in rodent TBI models .…”

“…20,21 Since many SRF effector genes encode TFs, this results in a second gene expression wave involved in modulation of learning and memory, synaptic plasticity as well as neuro-behavioral changes such as hyperactivity and modulated anxiety. [23][24][25] So far, selected IEGs such as cFos, cJun, and Egr1 were found upregulated by TBI in humans 26,27 and in rodent TBI models. [28][29][30][31][32] However, a functional role of SRF or one of these IEGs in TBI has not been described.…”

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

“…For example, Ca 2+ -dependent phosphorylation of the nuclear transcription factor CREB at Ser 133 leads to the transcription of immediate-early genes encoding multiple proteins (e.g., c-fos, BDNF, homer1a) that play key roles in learning and memory (Bading, 2013, Benito et al, 2011, Dolmetsch, 2003, Flavell & Greenberg, 2008. Multiple neuropsychiatric disorders are associated with disruptions in activity-dependent gene expression (Ebert & Greenberg, 2013, Gallo et al, 2018, and these disorders have been linked to mutations in Ca 2+ signaling proteins, such as L-type calcium channels (LTCCs) and calcium/calmodulin-dependent protein kinase II (CaMKII) (Akita et al, 2018, Chia et al, 2018, Kury et al, 2017, Limpitikul et al, 2016, Moon et al, 2018, Nyegaard et al, 2010, Pinggera et al, 2015, Pinggera et al, 2017, Pinggera & Striessnig, 2016, Proietti Onori et al, 2018, Stephenson et al, 2017. For example, Timothy Syndrome is caused by mutations in the CaV1.2 LTCC a1 subunit that disrupt neuronal excitation-transcription (E-T) coupling (Li et al, 2016), contributing to the neurobehavioral symptoms of this complex multi-system disorder, including autism spectrum disorder (ASD).…”